Flavan‐3‐ol Microbial Metabolites Modulate Proteolysis in Neuronal Cells Reducing Amyloid‐beta (1‐42) Levels

INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegeneration characterized by extensive protein aggregation and deposition in the brain, associated with defective proteasomal and autophagic‐lysosomal proteolytic pathways. Since current drugs can only reduce specific symptoms, the identification of novel treatments is a major concern in AD research. Among natural compounds, (poly)phenols and their derivatives/metabolites are emerging as candidates in AD prevention due to their multiple beneficial effects. This study aims to investigate the ability of a selection of phenyl‐γ‐valerolactones, gut microbiota‐derived metabolites of flavan‐3‐ols, to modulate the functionality of cellular proteolytic pathways. METHODS AND RESULTS: Neuronal SH‐SY5Y cells transfected with either the wild‐type or the 717 valine‐to‐glycine amyloid precursor protein mutated gene are used as an AD model and treated with 5‐(4ʹ‐hydroxyphenyl)‐γ‐valerolactone, 5‐(3ʹ,4ʹ‐dihydroxyphenyl)‐γ‐valerolactone and 5‐(3ʹ‐hydroxyphenyl)‐γ‐valerolactone‐4ʹ‐sulfate. Combining in vitro and in silico studies, it is observed that the phenyl‐γ‐valerolactones of interest modulated cellular proteolysis via proteasome inhibition and consequent autophagy upregulation and inhibited cathepsin B activity, eventually reducing the amount of intra‐ and extracellular amyloid‐beta (1‐42) peptides. CONCLUSION: The findings of this study establish, for the first time, that these metabolites exert a neuroprotective activity by regulating intracellular proteolysis and confirm the role of autophagy and cathepsin B as possible targets of AD preventive/therapeutic strategies.